The research continues our immunogenetic studies on the genes of the major histocompatibility complex (RT1) and of the growth and reproduction complex (grc) in the rat and broadens our strategy to include molelcular and cellular biological approaches. Our long-term objectives are to characterize the genes in the grc and those in its vicinity and to study the relationship between embryogenesis and carcinogenesis. These objectives will be pursued in the context of two specific aims. (1) The molecular genetics of the.Rt1.E-grc-T1a region will be investigated. The RT1 polymorphism of grc and grc+ DNA will be explored using a variety of molecular probes. This will be followed by fine structure mapping of the RT1.E-grc-T1a region, cloning genomic libraries from grc and grc+ DNA and identification of the genes encoded by the grc region. (2) The increased susceptibility to cancer induced by chemical carcinogens in grc-bearing rats will be investigated to determine its biochemical and genetic bases. The grc rats have the biochemical abnormalities associated with the development of cancer, and their role in the pathogenesis of cancer will be explored in whole animals and in a fibroblast tissue culture system. Its genetic basis will be confirmed by examining the segregation of enhanced susceptibility to cancer with the grc in a backcross system involving susceptible and resistant strains. Study of the grc will provide unique insights into the pathology of morphogenesis and its attendant physiological consequences and into the genetic and biochemical bases for the susceptibility to cancer. The association among the grc, congenital defects and enhanced susceptibility to cancer provides the first experimental system for establishing definitively the relationship between embryogenesis and carcinogenesis and for defining it in genetic and biochemical terms. The clinical implications are quite wide-ranging, since these studies could lead to the very early diagnosis of susceptibility to cancer and to the implementation of the appropriate strategy for the care of susceptible patients long before any clinical signs or symptoms of cancer developed.